Postoperative fever after liver resection: Incidence, risk factors, and characteristics associated with febrile infectious complication

Purpose To evaluate the incidence and risk factors of postoperative fever (POF) after liver resection. In patients with POF, predictors of febrile infectious complications were determined. Methods A total of 797 consecutive patients undergoing liver resection from January 2015 to December 2019 were retrospectively investigated. POF was defined as body temperature ≥ 38.0°C in the postoperative period. POF was characterized by time of first fever, the highest temperature, and frequency of fever. The Institut Mutualiste Montsouris (IMM) classification was used to stratify surgical difficulty, from grade I (low), grade II (intermediate) to grade III (high). Postoperative leukocytosis was defined as a 70% increase of white blood cell count from the preoperative value. Multivariate analysis was performed to identify risk factors for POF and predictors of febrile infectious complications. Results Overall, 401 patients (50.3%) developed POF. Of these, 10.5% had the time of first fever > postoperative day (POD) 2, 25.9% had fever > 38.6°C, and 60.6% had multiple fever spikes. In multivariate analysis, risk factors for POF were: IMM grade III resection (OR 1.572, p = 0.008), Charlson Comorbidity Index score > 3 (OR 1.872, p < 0.001), and serum albumin < 3.2 g/dL (OR 3.236, p = 0.023). 14.6% patients developed infectious complication, 21.9% of febrile patients and 7.1% of afebrile patients (p < 0.001). Predictors of febrile infectious complications were: fever > 38.6°C (OR 2.242, p = 0.003), time of first fever > POD2 (OR 6.002, p < 0.001), and multiple fever spikes (OR 2.039, p = 0.019). Sensitivity, specificity, positive predictive value and negative predictive value for fever > 38.6°C were 39.8%, 78.0%, 33.7% and 82.2%, respectively. A combination of fever > 38.6°C and leukocytosis provided high specificity of 95.2%. Conclusion In this study, we found that IMM classification, CCI score, and serum albumin level related with POF development in patients undergone liver resection. Time of first fever > POD2, fever > 38.6°C, and multiple fever spikes indicate an increased risk of febrile infectious complication. These findings may aid decision-making in patients with POF who require further diagnostic workup.

Variables Body temperature was measured with a thermometer via the tympanic route, at least four times a day during the postoperative period. Postoperative fever was defined as a body temperature higher than or equal to 38.0˚C in the postoperative period. Fever was further categorized as being (1) the time of first POF (� POD2 versus > POD2); (2) maximum body temperature (< 38.6˚C versus > 38.6˚C), and (3) single versus multiple fever spikes. Infections were classified according to anatomical site (eg, surgical site, lung, urinary tract, and bloodstream). Surgical site infection was defined as a condition in which purulent discharge was observed from any incision or surgical space, with or without a positive bacterial culture. Lung, bloodstream and urinary tract infections were diagnosed based on the presence of bacteria in the discharge from the pleural cavity, sputum, blood, or urine, In some cases, the diagnosis was based on physician's judgment in patients who presented with typical signs of infection, regardless of microbiological evidence [20,21]. The model for end-stage liver disease (MELD) score was calculated using the formula: MELD = 9.57 × log e (creatinine mg/dL) + 3.78 × log e (total bilirubin mg/dL) + 11.20 × log e (international normalized ratio, INR) + 6.43 [22]. Resection of less than three contiguous Couinaud segments was defined as minor liver resection, and resection of three or more contiguous Couinaud segments as major liver resection [23]. Liver resections were categorized into 3 levels of difficulty (low, intermediate and high) according to the Institut Mutualiste Montsouris (IMM) classification [24]. Grade I included wedge resection and left lateral sectionectomy. Grade II represented the intermediate level with anterolateral segmentectomy (IVb, V, VI, II, III) and left hepatectomy. Grade III represented the most technically advanced level including posterosuperior segmentectomy (I, IVa, VII, VIII), right posterior sectionectomy, right hepatectomy, extended right hepatectomy, central hepatectomy, and extended left hepatectomy. When multiple resections of varied difficulty were performed simultaneously, the liver resection was classified according to the most difficult procedure [25,26]. Comorbidities before liver resection was determined using the Charlson Comorbidity Index (CCI) [27]. The CCI scores were summed for each patient and grouped into two categories: CCI score � 3, and CCI score > 3. Pulmonary function test with measurement of forced expiratory volume in one second (FEV 1 ) was recorded. The determination of the postoperative white blood cell count was made on the basis of the value after the 4th day after liver resection [14]. Postoperative leukocytosis was defined as a 70% increase of white blood cell count from the preoperative value.
The operative procedures have been described elsewhere [28,29]. Liver transection was performed using the tissue-fracture technique or using an energy device. Laparoscopic resection was successfully performed in 316 patients (39.6%). The techniques of inflow occlusion, either hemihepatic vascular occlusion or the Pringle maneuver, were applied [30].
The patients were carefully monitored after the surgery. A broad-spectrum prophylactic antibiotic was administered for 1~3 days. For patients who have clinical signs suggestive of infectious complication, a routine workup including chest radiography, sputum, drains, urine, wounds, and blood cultures was selectively arranged, depending on patients' clinical conditions. Perioperative incentive spirometry was performed to prevent atelectasis and pneumonia. Patients are discharged home when adequate mobilization, toleration of a solid diet, and pain control with oral medication are achieve.

Statistical analysis
Variables were presented as mean (standard deviation) or number (percentage) as appropriate. The χ 2 test or Fisher exact test with Yates correction was used to compare differences in categorical variables when appropriate. Continuous variables were compared using Student's t-test. Continuous variables are dichotomized for disease risk discrimination and for decision making in clinical practice. Receiver operating characteristic (ROC) curve analysis was used to obtain optimal cutoff values for continuous variables. For (i) POF and (ii) postoperative leukocytosis as predictors of febrile infectious complication, the best cutoff values were body temperature of 38.6˚C, and a 70% increase in white blood cell count from preoperative baseline, respectively. Multivariate logistic regression analysis was used to evaluate factors related to POF, and to determine risk factors related with infectious complication in patients with POF. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. Statistical analyses were performed using IBM SPSS software (version 25.0; SPSS Inc., Chicago, IL). A p value < 0.05 was considered statistically significant.

Results
During the study period, 797 patients underwent liver resection for benign or malignant diseases were included. The main characteristics of the patient were listed in Table 1. Regarding the indication for liver resection, 719 cases (90.2%) were performed for malignant diseases and 78 (9.8%) for benign diseases. Of the malignant group, 594 (82.6%) were for hepatocellular carcinoma and 64 (8.9%) for colorectal liver metastasis. In the benign group, 25 (32%) were for hemangioma and 14 (20%) for focal nodular hyperplasia. The first episode of POF occurred within POD1 for 70.6% of febrile patients (Fig 2). Fever > 38.6˚C occurred in 104 patients (25.9%). Multiple fever spikes developed in 243 patients (60.6%). While there were only 20 patients (12.7%) with fever > 38.6˚C in the singlespike group, 84 patients (34.6%) with multiple fever spikes had fever > 38.6˚C (p < 0.001) (Fig 3).

Risk factors for postoperative fever
In univariate analysis, six factors were found to be significantly related to the development of POF (Table 2). Postoperative fever rate increased with the IMM classification difficulty grading, from 45.2% in the grade I group, to 50.0% in the grade II group, to 57.6% in the grade III group (p = 0.003). Postoperative fever rate increased with the CCI score, from 37.3% in the 0-1 score group, to 44.6% in the 2 to 3 score group, and 59.5% in the > 3 score group (p < 0.001). Serum albumin level was another variable affecting the prevalence of POF. Patients with preoperative serum albumin level < 3.2 g/dL had 78.6% POF compared with 49.3% in the � 3.2 g/dL group (p = 0.004). Open hepatectomy patients had a 53.4% prevalence of POF vs 45.6% in laparoscopic hepatectomy patients (p = 0.030). In patients with FEV1-predicted percentage < 95%, 54.8% of patients had POF vs 46.0% in the FEV1-predicted percentage � 95% group (p = 0.019). Blood transfusion also had a role in POF with 55.9% of transfused patients developing fever vs 47.8% of non-transfused patients (p = 0.036)). Multivariate analysis showed that IMM classification grade III (OR 1.572, 95% CI 1.125-2.197, p = 0.008), CCI score > 3 (OR 1.872, 95% CI 1.325-2.645, p < 0.001), and serum albumin < 3.2 g/dL (OR 3.236, 95% CI 1.174-8.918, p = 0.023) were independent risk factors related to POF.

Outcome of patients with postoperative fever
Of the 797 patients, 116 (14.6%) developed infectious complications Febrile complications developed in 21.9% patients with POF. There were 28 (7.1%) cases of infection in the no-fever group. Infectious complications was significantly higher in patients with POF compared to those without fever (21.9% versus 7.1%) (p < 0.001).
For patients with POF, the relationship between fever characteristic and febrile infectious complication was shown in Table 3. Patients with time of first fever > POD 2 and with

PLOS ONE
fever > 38.6˚C had significantly higher incidences of febrile infectious complications (p < 0.001 and p = 0.001, respectively) and positive bacterial cultures (p < 0.001 and p = 0.001, respectively). Patients with multiple fever spikes also tended to have increased incidence of infectious complications than those with a single fever spike, but the difference did not reach statistical significance (p = 0.058). The most common febrile complication was surgical site infection (47.7%). Pulmonary (including pleural cavity) infection was the second most common complication (35.2%). Blood stream infection with sepsis developed in 12.5% of all patients with POF. There was two cases of mortality (2.2%) in patients with POF, one case with postresectional liver infarction with sepsis, and one case with severe biliary tract infection and liver failure. Meanwhile, there was no cases of non-infectious febrile complications such as deep vein thrombosis or pulmonary embolism in any patients with POF.

Length of hospital stay and hospital cost
Patients with first episode of fever after POD 2 had significantly longer postoperative hospital stay than patients with fever before POD 2 (12.

Discussion
Postoperative fever is known to occur after all types of major surgical procedures with abdominal and chest procedures result in the highest incidence [6,7,10]. However, to date, the occurrence of fever following liver resection has not been studied. The results of the current study indicate that POF occurs in 50.3% of patients following liver resection. This incidence is slightly higher than those reported in the literature for patients undergoing major abdominal surgery, which ranged from 13% to 43% [7,31,32]. Fever in patients after an operation can have several causes at once, and infectious and noninfectious causes can coexist. In our study, in most patients who developed fever after liver resection, the cause is not determined. Many can be speculated to be related to tissue trauma, transfusion reaction, pulmonary atelectasis, intraabdominal fluid accumulation, transient bacteremia, or other self-limiting pathologies [5,33,34]. In our study, based on a large case series and using a multivariate analysis, we define three independent risk factors related to the development of POF. Postoperative fever was found to be more common in patients undergoing difficult types of liver resection (IMM classification grade III resection). The IMM classification is a recently reported three-level classification of the difficulty of liver resection, classifying the difficulty of the operation as low (grade I), intermediate (grade II), and high (grade III) [24]. This classification was found to be useful for stratifying surgical complexity for laparoscopic liver resection as well as open liver resection [25]. Kawaguchi et al [24] reported that the rates of major complications were highest in grade III compared to those of grade I and II. In the IMM classification, grade III resection represents the highly advanced level of surgical difficulty, including posterosuperior segmentectomy, right posterior sectionectomy, right hepatectomy, central hepatectomy, extended right hepatectomy, and extended left hepatectomy. The duration of the operation, blood loss, and morbidities differed between the three grades and gradually increased from grades I to III. The reasons why larger or complex surgery has a greater possibility of POF may be due to (1) a greater amount of tissue damage with an increased release of inflammatory cytokines, and (2) a large amount of fluid collection in a larger dead space after operation than ordinary surgery [9,[35][36][37]. In addition, resection of liver posterior superior segments (segments 1, 4a, 7, 8) is particularly related to the development of subphrenic fluid accumulation, pleural effusion and subsequent infectious complications [38][39][40][41]. Adequate drainage after resection in these patients is particularly important to avoid clinical symptoms associated with perihepatic fluid collection, including fever and/or abdominal discomfort [42]. The Charlson Comorbidity Index (CCI) was developed to predict the prognosis of admitted patients by assessing the number of certain comorbidities and their severity and has been widely used to assess the degree of comorbidity burden [43,44]. The CCI system records some important comorbidity closely relevant in the context of elective liver surgery, including coexisting liver disease, chronic pulmonary disease, peptic ulcer disease, diabetes, moderate-tosevere renal disease and tumor. Ulyett et al [45] indicated that in patients undergoing liver resection, a CCI score > 4 is independently associated with the development of Clavien-Dindo grade III-V complications. Walid et al [8] has indicated that in patients undergoing spine surgery, POF rate increased with the CCI score. In our study we found that a CCI score > 3 is associated with a higher risk of development of POF.
In our study, a low level of serum albumin was found to be another factor related to the development of POF. An association between hypoalbuminemia and POF has been reported previously [46][47][48]. We hypothesized that serum albumin level negatively affected the POF prevalence mainly in three ways. 1) In patient undergoing liver resection and with hypoalbuminemia, fluid accumulation in the abdomen or pleural cavity is more likely to occur. 2) Studies have reported that in febrile patients, a lower serum albumin level is a predictive factor for infection. Lower albumin levels can lead to insufficient immunoglobulin synthesis, which weakens the immune system [46].; 3) Albumin has the potential to mobilize polyunsaturated fatty acids and aid in the formation of several anti-inflammatory lipids. Therefore, low levels of serum albumin may tend to pro-inflammatory status [49]. In our study, the high odds ratio of 3.23 in the prediction of POF make this a factor of high clinical relevance and easily utilized, as this data is usually known preoperatively. In patients with hypoalbuminemia, adequate replacement of albumin and fresh frozen plasma is necessary and perioperative intravenous fluids should be restricted properly [50].
Prior studies of knee, spine, and general surgery procedures have reported that fevers after POD 2, lasting longer than 24 hours, peaking above 38.9˚C, or multiple fever spikes may all be more a sign of an infectious complication [4,37,[51][52][53][54]. There were few studies on the relationship between fever, infection, and other postoperative outcomes in patients who undergo liver surgery. In a study of risk factors related to infections following living donor liver transplantation, Elkholy et al [55] indicated that fever was an independent predictor of early infectious complication. In our study, the incidence of infection in patients with POF was 24.5%. Three characteristics of the fever: time of first POF (POD � 2 versus POD > 2), highest body temperature (� 38.6˚C versus > 38.6˚C) and frequency of fever (single versus multiple) are independent predictors of febrile infectious complication (Table 4). We might be particularly aware of the possibility of infection in patients with these features, and careful evaluation should be performed for optimal control of fever. A fever workup directed by additional clinical findings for these patients can be determined individually.
In our study, analyses concerning the sensitivity, specificity, PPV, and NPV of fever characteristics as predictors of febrile infectious complications were performed (Table 5). Sensitivity and specificity, PPV and NPV for fever > 38.6˚C were 39.8%, 78.0%, 33.7% and 82.2%, respectively. Previously Vermeulen et al. [56] reported a study of 284 patients who underwent general, trauma, vascular and gastroinestinal surgery to determine the diagnostic accuracy of POF as a predictor of infectious complication. Their results revealed that a temperature �38.0˚C as cutoff point yielded a sensitivity of 37%, a specificity of 80%, a PPV of 12% and a NPV of 95%. In liver resection, postoperative leukocytosis, reflected by a >20% increase in the white blood cell count from the preoperative value, was considered an early sign of infection [14]. In our study, ROC curve analysis indicated that a 70% increase in white blood cell count from preoperative baseline is an optimal leukocytosis cut-off value as a predictor of febrile infectious complication, yielding a sensitivity of 43.2% and a specificity of 79.7%. A combination of fever > 38.6˚C with leukocytosis provided a high specificity of 95.2%. These sensitivity/specificity/PPV/NPV analyzes can further help guide the clinician and enable the application of these data.
Our study's strengths include the large sample size and included a representative population of patients undergoing liver resection, with hepatectomy performed by an experience surgical team in a recent short period of time, which adds homogeneity to this series. Nevertheless, there are limitations to our study. First, this was a retrospective study, which has inherent biases. Information on compliance with the fever management protocol is lacking. Possible missed infections may exist due to the fact that some patients who developed fever may not be worked up for a possible cause, and the determination of workup components was based on the clinical impression of the physician to the patient. Second, the course of fever may be affected by aspects of clinical management, such as antibiotic and antipyretic use. Third, it is possible that in some cases a first flare of fever occurred after discharge and was not included in the analysis. These factors were not addressed in our study, which could limit the study. However, this study provides preliminary data regarding the development of fever in patients during hospitalization after liver resection surgery that can be used as an aid to guide future research. Further prospective studies with internal or external validation are required.

Conclusion
In this case-series study, we found that contributing factors related with POF in patients undergoing liver resection were: IMM classification grading, CCI score, and serum albumin level. In addition, first time fever after POD 2, fever > 38.6˚C, and fever with multiple spikes may indicate an increased risk of infectious complication. These parameters may be useful discriminators for potential risk of febrile infectious complication in patients undergoing liver resection with POF and may also aid decision-making in patients who require further diagnostic workup.